Phase transfer catalyzed glycosidation of an indolocarbazole

ABSTRACT

The present invention relates to a novel glycosidation process to make intermediates useful in the preparation of indolopyrrolocarbazole derivatives which inhibit the growth of tumor cells and are therefore useful in the treatment of cancer in mammals, and the like.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to a novel glycosidation process tomake intermediates useful in the preparation of indolopyrrolocarbazolederivatives which inhibit the growth of tumor cells and are thereforeuseful in the treatment of cancer in mammals, and the like.

[0002] In the field of cancer chemotherapy, a large number of compoundshave already been put to practical use as antitumor agents. However, aneed continues for the development of more efficacious compounds thatwork against a variety of tumors (see the Proceedings of the 47thGeneral Meeting of the Japan Cancer Society, pp. 12-15 (1988)). Thisneed has led to the development of indolocarbazole derivatives. (SeeU.S. Pat. Nos. 4,487,925; 4,552,842; 4,785,085; 5,591,842 and 5,922,860;Japanese Patent No. 20277/91; Journal of Antibiotics, Vol. 44, pp.723-728 (1991); WO91/18003; WO 98/07433; and EP0545195 A1.) Thesecompounds have been shown to act as topoisomerase inhibitors andtherefore useful in the treatment of cancer (Cancer Chemother.Pharmacol. 34 (suppl): S41-S45 (1994)).

[0003] The success of these compounds in treating numerous cancers hasnecessitated the development of improved methods for their syntheses.(See Bioorg. & Med. Chem. Letters 2000, 10, 419; Tetrahedron 1997, 53,5937; Tetrahedron 1997, 53, 585; and Synthesis 1976, 414.) Thepreviously known methods, however, suffer from numerous problems,including the use of undesirable solvents, mercury or silver salts, lowyields and formation of unwanted side-products necessitating tedious orprotracted purification steps.

[0004] An object of this invention therefore is to provide a novel routeto intermediates useful in the preparation ofindolopyrrolocarbazole-derived antitumor substances while overcoming theproblems inherent in the previously known syntheses.

SUMMARY OF THE INVENTION

[0005] The present invention is a novel glycosidation process to makeintermediates useful in the preparation of indolopyrrolocarbazolederivatives which inhibit the growth of tumor cells and are thereforeuseful in the treatment of cancer in mammals, and the like, such asthose of Formula I below.

DETAILED DESCRIPTION OF THE INVENTION

[0006] An embodiment of the present invention is illustrated by aprocess for the preparation of a compound of Formula I,

[0007] wherein

[0008] Q is O, N—R, S, or CH₂;

[0009] X¹ and X² are independently selected from:

[0010] 1) H,

[0011] 2) halogen,

[0012] 3) OH,

[0013] 4) CN,

[0014] 5) NC,

[0015] 6) CF₃,

[0016] 7) (C═O)NO₂,

[0017] 8) (C═O)C₁-C₆ alkyl,

[0018] 9) (C═O)OC₁-C₆ alkyl,

[0019] 10) OCH₂OCH₂CH₂Si(CH₃)₃,

[0020] 11) NO₂,

[0021] 12) 9-fluorenylmethylcarbonyl,

[0022] 13) NR₅R₆,

[0023] 14) OC₁-C₆ alkyl,

[0024] 15) C₁-C₆ alkyl,

[0025] 16) C₁-C₆ alkylenearyl, and

[0026] 17) OC₁-C₆ alkylenearyl;

[0027] R and R¹ are independently:

[0028] 1) H,

[0029] 2) (C═O)C₁-C₆ alkyl,

[0030] 3) (C═O)CF₃,

[0031] 4) (C═O)OC₁-C₆ alkyl,

[0032] 5) 9-fluorenylmethylcarbonyl,

[0033] 6) a furanose group, or

[0034] 7) a pyranose group,

[0035]  so long as one of R and R¹ is a furanose group or a pyranosegroup;

[0036] R² and R³ are independently OH or H, or

[0037] R² and R³ are taken together to form an oxo group;

[0038] R⁴ is:

[0039] 1) H,

[0040] 2) C₁-C₁₀ alkyl,

[0041] 3) CHO

[0042] 4) (C═O)C₁-C₁₀ alkyl,

[0043] 5) (C═O)OC₁-C₁₀ alkyl,

[0044] 6) C₀-C₁₀ alkylenearyl, or

[0045] 7) C₀-C₁₀ alkylene-NR⁵R⁶;

[0046] R⁵ and R⁶ are independently:

[0047] 1) H,

[0048] 2) (C₁-C₈ alkyl)-(R⁷)₂,

[0049] 3) (C═O)O(C₁-C₈ alkyl),

[0050] 4) 9-fluorenylmethylcarbonyl,

[0051] 5) OCH₂OCH₂CH₂Si(CH₃)₃,

[0052] 6) (C═O)(C₁-C₈ alkyl),

[0053] 7) (C═O)CF₃, or

[0054] 8) (C₂-C₈ alkenyl)-(R⁷)₂, or

[0055] R⁵ and R⁶ are taken together with the nitrogen to which they areattached to form N-phthalimido;

[0056] R⁷ is:

[0057] 1) H,

[0058] 2) OH,

[0059] 3) OC₁-C₆ alkyl, or

[0060] 4) aryl, said aryl optionally substituted with up to two groupsselected from OH, O(C₁-C₆ alkyl), and (C₁-C₃ alkylene)-OH;

[0061] which comprises the steps of:

[0062] (a) reacting a furanose or a pyranose with an activating reagentto produce an activated sugar; and

[0063] (b) coupling the activated sugar with a compound of Formula IV

[0064] wherein R^(1a) is H if Q is O, S, CH₂, or N—R and R is not H,otherwise R^(1a) is selected from R¹;

[0065] in the presence of an aqueous solution of alkali hydroxide and aphase transfer catalyst in a biphasic system to produce the compound ofFormula I.

[0066] Another embodiment is the process described above, wherein

[0067] R and R¹ are independently selected from a furanose group ofFormula IIA or a pyranose group of Formula IIB, when R or R¹ is definedas a furanose group or a pyranose group, respectively;

[0068] R⁸ is independently selected from:

[0069] 1) hydrogen,

[0070] 2) C₁-C₆ alkyl,

[0071] 3) OH,

[0072] 4) halogen,

[0073] 5) O(C₁-C₆ alkyl),

[0074] 6) O(C₁-C₆ alkylene)-aryl,

[0075] 7) OSO₂(C₁-C₆ alkyl),

[0076] 8) OSO₂aryl,

[0077] 9) OCH₂CH₂CH₂Si(CH₃)₃,

[0078] 10) O(C═O)(C₁-C₆ alkyl),

[0079] 11) O(C═O)CF₃,

[0080] 12) azido, or

[0081] 13) NR⁵R⁶, or

[0082] two R⁸'s on the same carbon are taken together to be oxo, ═N—R⁵,or ═N—R⁷; and

[0083] the furanose or pyranose in Step (a) is a furanose of FormulaIIIA or a pyranose of Formula IIIB, respectively;

[0084] In another embodiment, the activating reagent in Step (a) isselected from an acid halide, a sulfonate, a phosphate, a sulfate, aborate, or an acetate and the biphasic system in Step (b) is comprisedof an organic solvent selected from a hydrocarbon, a nitrile, an ether,a halogenated hydrocarbon, a ketone, or an apolar aprotic solvent.

[0085] Yet another embodiment is the process described above wherein theactivating reagent is selected from SOCl₂ or oxalyl chloride.

[0086] A further embodiment is the process described above wherein thebiphasic system is comprised of methyl-t-butyl ether, dichloromethane,or trifluorotoluene.

[0087] In still another embodiment the phase transfer catalyst in Step(b) is (R^(a))₄M⁺A⁻;

[0088] R^(a) is independently H or C₁-C₁₈ aliphatic hydrocarbon;

[0089] M is N or P; and

[0090] A is OH, F, Br, Cl, I, HSO₄, CN, MeSO₃, or PhCH₂CO₂.

[0091] A preferred embodiment is the process described above wherein thephase transfer catalyst is tricaprylmethyl ammonium chloride.

[0092] Another preferred embodiment is the process according to thedescription above, wherein the aqueous solution of alkali hydroxide inStep (b) has a concentration of about 5% to about 95% w/w and the alkalihydroxide is selected from lithium hydroxide, sodium hydroxide,potassium hydroxide, and cesium hydroxide.

[0093] Also favored is the process wherein the aqueous solution ofalkali hydroxide has a concentration of about 45% to about 50% w/v andthe alkali hydroxide is potassium hydroxide or sodium hydroxide.

[0094] A more preferred embodiment is a process for the preparation of acompound of Formula V,

[0095] wherein

[0096] R⁴ is:

[0097] 1) H,

[0098] 2) C₁-C₁₀ alkyl,

[0099] 3) CHO

[0100] 4) (C═O)C₁-C₁₀ alkyl,

[0101] 5) (C═O)OC₁-C₁₀ alkyl,

[0102] 6) C₀-C₁₀ alkylenearyl, or

[0103] 7) C₀-C₁₀ alkylene-NR⁵R⁶;

[0104] R⁵ and R⁶ are independently:

[0105] 1) H,

[0106] 2) (C₁-C₈ alkyl)-(R⁷)₂,

[0107] 3) (C═O)O(C₁-C₈ alkyl),

[0108] 4) 9-fluorenylmethylcarbonyl,

[0109] 5) OCH₂OCH₂CH₂Si(CH₃)₃,

[0110] 6) (C═O)(C₁-C₈ alkyl),

[0111] 7) (C═O)CF₃, or

[0112] 8) (C₂-C₈ alkenyl)-(R⁷)₂, or

[0113] R⁵ and R⁶ are taken together with the nitrogen to which they areattached to form N-phthalimido;

[0114] R⁷ is:

[0115] 1) H,

[0116] 2) OH,

[0117] 3) OC₁-C₆ alkyl, or

[0118] 4) aryl, said aryl optionally substituted with up to two groupsselected from OH, O(C₁-C₆ alkyl), and (C₁-C₃ alkylene)-OH;

[0119] R⁹ is:

[0120] 1) H,

[0121] 2) C₁-C₆ alkyl,

[0122] 3) (C₁-C₆ alkylene)-aryl,

[0123] 4) SO₂(C₁-C₆ alkyl),

[0124] 5) SO₂aryl,

[0125] 6) CH₂OCH₂CH₂Si(CH₃)₃,

[0126] 7) (C═O)(C₁-C₆ alkyl), or

[0127] 8) (C═O)CF₃;

[0128] which comprises the steps of:

[0129] (a) reacting a sugar derivative of Formula VI with an acidchloride to produce the activated sugar; and

[0130] (b) coupling the activated sugar with a compound of Formula VII

[0131]  in the presence of an aqueous solution of an alkali hydroxideand tricaprylmethyl ammonium chloride in t-butyl methyl ether to producethe compound of Formula V.

[0132] And yet another preferred embodiment is a process for thepreparation of a compound of Formula VIII,

[0133] which comprises the steps of:

[0134] (a) reacting a sugar derivative of Formula IX with thionylchloride to produce the activated sugar;

[0135] (b) coupling the activated sugar with a compound of Formula X

[0136]  in the presence of an aqueous solution of potassium hydroxide orsodium hydroxide and tricaprylmethyl ammonium chloride in t-butyl methylether to form the glycosidated compound XI;

[0137] (c) deprotecting the glycosidated product XI by reacting it withcatalytic palladium in the presence of hydrogen gas to form thedeprotected glycosidated product XII;

[0138] (d) reacting the deprotected glycosidated product XII with anaqueous solution of alkali hydroxide to form anhydride XIII; and

[0139] (e) reacting anhydride XIII with 2-hydrazino-1,3-propanediol toproduce the compound of Formula VIII.

[0140] Also preferred is the process as described above to make acompound of Formula V wherein Step (A) is conducted in t-butyl methylether or tetrahydrofuran at a temperature of about −10° C. to about 30°C. and Step (B) is conducted at a temperature of about 10° C. to about40° C.

[0141] And a final embodiment is the process described above, whereinthe potassium hydroxide or sodium hydroxide in step (b) is added beforethe tricaprylmethyl ammonium chloride.

[0142] The compounds of the present invention may have asymmetriccenters, chiral axes, and chiral planes (as described in: E. L. Elieland S. H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons,New York, 1994, pages 1119-1190), and occur as racemates, racemicmixtures, and as individual diastereomers, with all possible isomers andmixtures thereof, including optical isomers, being included in thepresent invention. In addition, the compounds disclosed herein may existas tautomers and both tautomeric forms are intended to be encompassed bythe scope of the invention, even though only one tautomeric structure isdepicted.

[0143] When any variable (e.g. X¹, X², R⁸, R⁹ etc.) occurs more than onetime in any constituent, its definition on each occurrence isindependent at every other occurrence. Also, combinations ofsubstituents and variables are permissible only if such combinationsresult in stable compounds. Lines drawn into the ring systems fromsubstituents indicate that the indicated bond may be attached to any ofthe substitutable ring carbon atoms. If the ring system is polycyclic,it is intended that the bond be attached to any of the suitable carbonatoms on the proximal ring only.

[0144] It is understood that substituents and substitution patterns onthe compounds of the instant invention can be selected by one ofordinary skill in the art to provide compounds that are chemicallystable and that can be readily synthesized by techniques known in theart, as well as those methods set forth below, from readily availablestarting materials.

[0145] As used herein, “alkyl” is intended to include both branched,straight-chain, and cyclic saturated aliphatic hydrocarbon groups havingthe specified number of carbon atoms. For example, C₁-C₆, as in “C₁-C₆alkyl” is defined to include groups having 1, 2, 3, 4, 5, or 6 carbonsin a linear, branched, or cyclic arrangement. For example, “C₁-C₆ alkyl”specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, andso on, as well as cycloalkyls such as cyclopropyl, methylcyclopropyl,dimethylcyclobutyl, cyclobutyl, cyclopentyl, and cyclohexyl, and so on.The alkyl sbstituents may be unsubstituted or substituted with one tothree substituents selected from halogen, C₁-C₆ alkyl, OH, OC₁-C₆ alkyl,O(C═O)C₁-C₆ alkyl, O(C═O) OC₁-C₆ alkyl, amino, amido, CO₂H, CN, NO₂, N₃,C₁-C₆ perflouroalkyl, and OC₁-C₆ perflouroalkyl. “Alkoxy” represents analkyl group of indicated number of carbon atoms attached through anoxygen bridge.

[0146] The term “alkenyl” refers to a non-aromatic hydrocarbon radical,straight, branched or cyclic, containing from 2 to 10 carbon atoms andat least one carbon to carbon double bond. Preferably one carbon tocarbon double bond is present, and up to four non-aromatic carbon-carbondouble bonds may be present. Thus, “C₂-C₆ alkenyl” means an alkenylradical having from 2 to 6 carbon atoms. Alkenyl groups include ethenyl,propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight,branched or cyclic portion of the alkenyl group may contain double bondsand may be substituted if a substituted alkenyl group is indicated.

[0147] In certain instances, substituents may be defined with a range ofcarbons that includes zero, such as (C₀-C₆)alkylene-NR⁵R⁶. If R⁵ and R⁶are taken as H in this case, this definition would include NH₂, as wellas —CH₂NH₂, —CH₂CH₂NH₂, CH(CH₃)CH₂CH(CH₃)NH₂, —CH₂CH(NH₂)CH₃, and so on.It is intended in these cases that the substituent on the bivalentradical can be attached at any point and not limited to the terminalposition.

[0148] As used herein, “aryl” is intended to mean substituted andunsubstituted phenyl or naphthyl. If substituted, it may be substitutedwith one to three substituents selected from halogen, C₁-C₆ alkyl, OH,OC₁-C₆ alkyl, O(C═O)C₁-C₆ alkyl, O(C═O)OC₁-C₆ alkyl, amino, amido, CO₂H,CN, NO₂, N₃, C₁-C₆ perflouroalkyl, and OC₁-C₆ perflouroalkyl.

[0149] As appreciated by those of skill in the art, “halo” or “halogen”as used herein is intended to include chloro, fluoro, bromo and iodo.

[0150] When definitions such as “(C₁-C₈ alkyl)-(R⁷)₂” are used, it isintended that the variable R⁷ be attached at any point along the alkylmoiety. Therefore, if R⁷ is defined as OH in this case, the definitionwould include the following: CH₂OH, CH₂CH₂OH, CH(CH₃)CH(OH)CH₃,CH(CH₃)CH(OH) CH₂—CH(OH)CH₃, and so on.

[0151] The term “alkylene” and “alkenylene” simply refer to an alkyl oralkenyl group as defined above, respectively, of the specified number ofcarbons that is divalent. For example, “C₁-C₄ alkylene” includes —CH₂—,—CH₂CH₂—, —CH(CH₃)CH₂—, and so on.

[0152] The definitions of R and R¹ include furanose and pyranose sugarderivatives. Preferred sugar derivatives are O-protected pyranoses, suchas D-glucopyranose; 6-deoxy-6,6-difluoro-D-glucopyranose;6-deoxy-6-azido-D-glucopyranose; 6-amino-6-deoxy-D-glucopyranose;6-azido-D-glucopyranose; 6-amino-D-glucopyranose;4-deoxy-4,4-difluoro-6-deoxy-6-azido-D-glucopyranose;2-fluoro-D-glucopyranose; D-galactopyranose; 4-deoxy-D-galactopyranose;4-deoxy-D-glucopyranose; and 4-methoxy-D-glucopyranose. (see, forexamples, WO 98/07433, hereby incorporated by reference). Preferredfuranoses include xylofuranose, arabinofuranose, ribofuranose,allofuranose, and 2-deoxyribofuranoses.

[0153] R⁹ can generally be any known O-protecting group. Examples ofsuch protecting groups include, but are not limited to: benzyl,p-nitrobenzyl, tolyl, and the like. A more preferred protecting group isbenzyl (Bn), i.e., CH₂Ph. Other suitable protecting groups will be knownto those of skill in the art, examples of which can be found inProtective Groups in Organic Synthesis by Peter G. M. Wuts and TheodoraW. Greene; John Wiley & Sons, 3^(rd) ed. (1999).

[0154] As used herein, “biphasic system” refers to a two-phase solventsystem consisting of an aqueous phase and an organic phase.

[0155] The choice of activating reagent to activate the sugar forcoupling can be readily discerned by those skilled in the art. Examplesof such reagents include acid halides (such as SOCl₂, POCl₃, SOBr₂,POBr₃, PBr₃ and oxalyl chloride), sulfonyl halides, and so on. Thepreferred reagents are thionyl chloride and oxalyl chloride. The mostpreferred is thionyl chloride. Other useful reagents in the activationinclude triphenyl phosphine/I₂, and triphenylphosphine/azidodicarboxylate.

[0156] The appropriate solvent to be used in the reaction to activatethe sugar can be ascertained by the ordinary chemist. Preferred solventsare hydrocarbons (such as toluene, xylenes, heptane, and hexane),nitrites (such as acetonitrile), ethers (such as t-butyl methyl etherand tetrahydrofuran), halogenated hydrocarbons (such as methylenechloride, carbontetrachloride, chloroform, trifluorotoluene anddichlorobenzene) ketones (such as methyl isobutyl ketone and acetone),and apolar aprotic solvents (such as N,N-dimethylformamide and1-methyl-2-pyrrolidinone). More preferred solvents are t-butyl methylether and tetrahydrofuran. The most preferred solvent is t-butyl methylether.

[0157] The activation reaction can be performed at temperatures rangingfrom about −50° C. to about 200° C. The preferred temperatures are about−10° C. to about 30° C.

[0158] Similarly, the appropriate solvent to use in the biphasiccoupling reaction will be readily discernible to the skilled artisan.Appropriate solvents include hydrocarbons (such as toluene, xylenes,heptane, and hexane), nitrites (such as acetonitrile), ethers (such ast-butyl methyl ether and tetrahydrofuran), halogenated hydrocarbons(such as methylene chloride, carbontetrachloride, chloroform,trifluorotoluene and dichlorobenzene) ketones (such as methyl isobutylketone and acetone), and apolar aprotic solvents (such asN,N-dimethylformamide and 1-methyl-2-pyrrolidinone). The preferredsolvents are t-butyl methyl ether, dichloromethane, andtrifluorotoluene.

[0159] The coupling reaction can be performed at temperatures rangingfrom about −50° C. to about 200° C. The preferred temperatures are about0° C. to about 40° C.

[0160] The preferred bases for the coupling reaction are alkalihydroxides, such as lithium, sodium, potassium, and cesium hydroxide.Potassium hydroxide and sodium hydroxide are more preferred. The baseconcentration in water can vary from about 5% w/w to about 95% w/w. Themore preferred concentrations are about 45% to about 50% w/w.

[0161] The preferred phase transfer reagents in the coupling reactionare of the general formula (R^(a))₄M⁺A⁻, wherein Ra is independently Hor C₁-C₁₈ aliphatic hydrocarbon; M is N or P; and A is OH, F, Br, Cl, I,HSO₄, CN, MeSO₃, or PhCH₂CO₂. A preferred phase transfer catalyst istricaprylmethyl ammonium chloride. Other suitable phase transfercatalysts include, but are not limited to,tris-[2-(2-methoxyethoxy)ethyl]amine (TDA-1); BnEt₃N⁺Cl−; and(Bu)₃NH⁺HSO₄−.

[0162] Synopsis of Schemes

[0163] Scheme A illustrates one possible generalized approach to thepreparation of the glycosidation substrate A-6. Other approaches areknown in the art, some of which are taught by Kojiri et al. in U.S. Pat.No. 5,922,860 (issued Jul. 13, 2000) and hereby incorporated byreference. Scheme B shows the phase transfer catalyzed glycosidation ofA-6 to produce intermediates of type B-3. Schemes C and D show possiblefurther modifications to afford compounds known to be useful astopoisomerase inhibitors.

EXAMPLES

[0164] Examples provided are intended to assist in a furtherunderstanding of the invention. Particular materials employed, speciesand conditions are intended to be further illustrative of the inventionand not limiting of the reasonable scope thereof.

[0165] Intermediate 5, used in the glycosidation reaction of thisinvention, can be obtained by the method disclosed by Kojiri et al. inU.S. Pat. No. 5,922,860 (issued Jul. 13, 2000) and hereby incorporatedby reference. The procedure is outlined below in Examples 1 through 5.

Example 1

[0166] Preparation of the Compound Represented by Formula 1

[0167] 284 g of 6-benzyloxyindole was dissolved in 3 liters of THF, and2.7 liters of lithium hexamethyldisilazide (as a 1M solution in THF) wasadded thereto. After this mixture was stirred under an atmosphere ofnitrogen at −10° C. for 45 minutes, 3 liters of a ThF solutioncontaining 340 g of 2,3-dibromo-N-methylmaleimide was added dropwisethereto over a period of 1 hour. After completion of the addition, theresulting mixture was stirred at 0° C. for 15 minutes. The reactionmixture was poured into 10 liters of 2N hydrochloric acid and extractedwith 30 liters of ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium hydrogen carbonate and then asaturated aqueous solution of sodium chloride, dried and concentrated.The resulting residue was recrystallized from methanol to obtain desiredcompound 1. HRMS (m/z): found 410.0292, calcd 410.0266 [as C₂₀H₁₅N₂O₃Br]IR (KBr, cm⁻¹): 3330, 3318, 1762, 1701, 1606, 1511, 1450, 1165, 1135,1041, 794. ¹H-NMR (300 MHz, CDCl₃, δ ppm): 8.60(1H, brs), 7.96(1H, d,J=8.1 Hz), 7.94(1H, d, J=2.5 Hz), 7.33-7.47(5H, m), 7.00(1H, dd J=2.5,8.8 Hz), 6.97(1H, d, J=2.5 Hz), 5.13(2H, s), 3.16(3H, s).

Example 2

[0168] Preparation of the Compound Represented by Formula 2

[0169] 1.00 g of compound 1 obtained in Example 1, 637 mg ofdi-tert-butyl dicarbonate and 3 mg of 4-N,N-dimethylaminopyridine weredissolved in 200 mL of THF, and this solution was stirred at roomtemperature for 1 hour. After the reaction mixture was concentrated, theresulting residue was recrystallized from ethyl acetate-hexane to obtainthe desired compound (2). IR (KBr, cm⁻¹): 1740, 1714, 1614, 1527, 1487,1443, 1373, 1227, 1153. HRMS (m/z): found 510.0771, calcd 510.0791 [asC₂₅H₂₃N₂O₅Br] ¹H-NMR (300 MHz, CDCl₃, δ. ppm): 8.10(1H, s), 7.91(1H, d,J=2.3 Hz), 7.73(1H, d, J=8.9 Hz), 7.34-7.50(5H, m), 7.03(1H, dd, J=2.3,8.5 Hz), 5.16(2H, s), 3.18(3H, s), 1.68(9H, s).

Example 3

[0170] Preparation of the Compound Represented by Formula 3

[0171] 218.4 mg of 6-benzyloxyindole was dissolved in 20 mL of THF, and2.35 mL of lithium hexamethyldisilazide (as a 1M solution in THF) wasadded thereto. After this mixture was stirred under an atmosphere ofnitrogen at 0° C. for 15 minutes, 10 mL of a THF solution containing 500mg of the compound (2) obtained in Example 2 was added dropwise theretoover a period of 10 minutes. After completion of the addition, theresulting mixture was stirred at room temperature for 0.5 hour. Thereaction mixture was poured into 100 mL of 2N hydrochloric acid andextracted with 400 mL of ethyl acetate. The organic layer was washedwith water, a saturated aqueous solution of sodium hydrogen carbonateand then a saturated aqueous solution of sodium chloride, dried andconcentrated. The resulting residue was recrystallized fromtoluene-hexane to obtain the desired compound (3). HRMS (m/z): found653.2556, calcd 653.2526 [as C₄₀H₃₅N₃O₆] IR (KBr, cm⁻¹): 1740, 1701,1646, 1623, 1543, 1445, 1155. ¹H-NMR (300 MHz, CDCl₃, δ ppm): 8.41(1H,brs), 7.97(1H, s), 7.84(1H, brs), 7.68(1H, brs), 7.16-7.43(10H, m),6.98(1H, d, J=9.2 Hz), 6.85(1H, brs), 6.74(1H, d, J=9.2 Hz), 6.58(1H, d,J=9.2 Hz), 6.52(1H, d, J=9.2 Hz), 5.05(2H, s), 5.02(2H, s), 3.19(3H, s),1.67(9H, s).

Example 4

[0172] Preparation of the Compound Represented by Formula 4

[0173] 100 mg of the compound (3) obtained in Example 3 was dissolved in10 mL of methylamine (as a 40% solution in methanol), and this solutionwas stirred at room temperature for 30 minutes. After the reactionmixture was concentrated, the resulting residue was recrystallized fromdichloromethane-acetone-hexane to obtain 68.6 m of the desired compound(4). HRMS (m/z): found 553.1982, calcd 553.2002 [as C₃₅H₂₇N₃O₄] IR (KBr,cm⁻¹): 3419, 3350, 1759, 1697, 1620, 1533, 1454, 1383, 1292, 1167.¹H-NMR (300 MHz, DMSO-d₆, δ ppm): 11.48(2H, s), 7.62(2H, s),7.28-7.45(10H, m), 6.95(2H, d, J=1.2 Hz), 6.70(2H, d, J=8.7 Hz),6.39(2H, dd, J=1.2, 8.7 Hz), 5.04(4H, s), 3.03(3H, s).

Example 5

[0174] Preparation of the Compound Represented by Formula 5

[0175] 1.01 g of the compound (4) obtained in Example 4 and 456.1 mg of2,3-dichloro-5,6-dicyano-1,4-benzoquinone were dissolved in 50 mL oftoluene, and this solution was stirred at 110° C. for 40 minutes. Afterthe reaction mixture was returned to room temperature, the insolublematter was filtered off and washed with 30 mL of methanol. The residuewas recrystallized from dimethyl sulfoxide-dichloromethane-methanol toobtain the desired compound (5). HRMS (m/z): found 551.1829, calcd551.1845 [as C₃₅H₂₅N₃O₄] IR (KBr, cm⁻¹): 3257, 1740, 1675, 1620, 1571,1402, 1246, 1178. ¹H-NMR (300 MHz, DMSO-d₆, δ ppm): 11.46(2H, s),8.79(2H, d, J=8.5 Hz), 7.53(4H, d, 8.5 Hz), 7.35-7.44(8H, m), 7.02(2H,dd, 8.5, 0.8 Hz), 5.25(4H, s), 3.13(3H, s).

Example 6

[0176]

[0177] Step 1

[0178] 100 g (185 mmols) of 2,3,4,6-O-tetrabenzyl-D-glucopyranose (6-1)was combined with 360 mL of DMF at 23° C. and then cooled to 9° C.Thionyl chloride (16.2 mL; 222 mols) was added slowly over 15 minutes,during which time the temperature rose to 20° C. The solution was warmedto about 30° C. and aged for 1 hour. The solution was then cooled to−10° C. and 10% KOH w/w (about 150 mL) was added, during which time thetemperature did not exceed 0° C. The solution was warmed to 22° C. Theaqueous layer was extracted with t-butyl methyl ether (MTBE) (1×300 mL).The combined organic layers were then washed with brine (1×150 mL) andwater (1×200 mL). The solution was concentrated under reduced pressureto the 350 mL level and used in the next step without furtherpurification.

[0179] Step 2

[0180] 72 g (131 mmol) of compound 5 from Example 5 above were dissolvedin 600 mL of MTBE and stirred for 10 minutes at 23° C. The solution of6-2 made in Step 1 above was then added and, after 10 minutes, 45% w/waqueous KOH (300 mL) was added. After an additional 10 minutes, 40% w/wAliquat® 336 (72 g in 110 g MTBE) was added slowly over 22 minutes.Aliquat® 336 is a brand name of tricaprylmethylammonium chloride sold byAldrich Chemical Co., Inc., in Milwaukee, Wis. The solution was aged at23° C. for 6 hours and 350 mL of water were then added and allowed tomix for 5 minutes. The layers were separated and the aquoeus layer waswashed with MTBE (1×300 mL). The combined organic layers were thenwashed with 10% w/w citric acid (1×300 mL) and water (1×300 mL). Theorganic layer was stirred at 22° C. overnight during which time theproduct (6-3) began to crystallize. The solution was then concentratedat atmospheric pressure (bp 55° C.) to the 625 mL level. At this point,the solution was cooled to 23° C. and methanol (225 mL) was added slowlyover 1 hour. The slurry was then cooled to −5° C. and aged for 45minutes. The solids were isolated and washed with chilled 1:1methanol/MTBE (2×400 mL). Drying in vacuo at 25°−40° C. provided theproduct 6-3 with over 99% purity by liquid chromatography.

[0181] The following examples, taken from Kojiri et al. in U.S. Pat. No.5,922,860 and previously incorporated by reference, illustrate the useof the glycosidation products in the synthesis of a known topoisomeraseinhibitor (9).

Example 7

[0182] Preparation of the Compound Represented by Formula 7

[0183] 100 mg of compound 6-3 was dissolved in 6 mL ofchloroform-methanol (2:1), and a catalytic amount of palladium black wasadded thereto. This mixture was stirred under an atmosphere of hydrogenfor 2 hours. After the catalyst was filtered off, the filtrate wasconcentrated. The resulting residue was crystallized frommethanol-acetone-ethyl acetate-hexane, developed with Sephadex LH-20,eluted with chloroform-methanol-ethanol-tetrahydrofuran (5:2:2:1), andrecrystallized from acetone-methanol-hexane to obtain the desiredcompound (7). HRMS (m/z): found 533.1429, calcd 533.1434 [as C₂₇H₂₃N₃O₉] IR (KBr, cm⁻¹): 3328, 1733, 1683, 1678, 1540, 1417, 1126, 1081,611. ¹H-NMR (300 MHz, DMSO-d₆, δ ppm): 11.20(1H, s), 9.76(1H, s),9.74(1H, s), 8.88(1H, d, J=8.6 Hz), 8.80(1H, d, J=8.6 Hz), 7.18(1H, d,J=2.1 Hz), 6.99(1H, d, J=2.1 Hz), 6.82(1H, dd, J=2.1, 8.6 Hz), 6.80(1Hz), dd, J=2.1, 8.6 Hz), 5.97(1H, J=8.9 Hz), 5.86(1H, t, J=4.0 Hz),5.33(1H, d, J=4.9 Hz), 5.12(1H, d, J=4.3 Hz), 4.94(1H, d, J=5.2 Hz),4.02(1H, dd, J=3.0, 10.7 Hz), 3.94(1H, m), 3.78(1H, m), 3.52(2H, m),3.16(3H, s).

Example 8

[0184] Preparation of the Compound Represented by Formula 8

[0185] 1.2 g the compound (7) was dissolved in 40 mL of a 10% aqueoussolution of potassium hydroxide, and this solution was stirred at roomtemperature for 1 hour. The reaction mixture was neutralized by theaddition of 40 mL of 2N hydrochloric acid, and then extracted with 1liter of methyl ethyl ketone. The organic layer was washed with asaturated aqueous solution of sodium chloride, dried and concentrated.The resulting residue was recrystallized from acetone-heptane to obtainthe desired compound (8). HRMS (m/z): found 520.1147, calcd 520.1118 [asC₂₆H₂₀N₂O₁₀] IR (KBr, cm⁻¹): 3311, 1810, 1739, 1652, 1626, 1558, 1405,1091, 611. ¹H-NMR (300 MHz, DMSO-d₆, δ ppm): 11.4(1H, s), 9.95(1H, s),9.92(1H, s), 8.69(1H, d, J=7.7 Hz), 8.63(1H, d, J=7.7 Hz), 7.25(1H, d,J=1.5 Hz), 7.03(1H, d, J=1.5 Hz), 6.90(1H, dd, J=1.5, 7.7 Hz), 6.87(1H,d, J=1.5, 7.7 Hz), 6.06(1H, d, J=8.0 Hz), 5.95(1H, t, J=4.6 Hz),5.38(1H, d, J=5.1 Hz), 5.16(1H, d, J=5.2 Hz), 4.99(1H, d, J=5.2 Hz),3.30-4.10(6H, m).

Example 9

[0186] Preparation of the Topoisomerase Inhibitor Represented by Formula9

[0187] 500 mg of compound 8 was dissolved in 50 mL of DMF, and 152 mg of2-hydrazino-1,3-propanediol was added thereto. This mixture was stirredat 80° C. for 1 hour. After the reaction mixture was concentrated, theresulting residue was purified with Sephadex LH-20(chloroform-methanol-ethanol-water=5:2:2:1) to obtain compound 9. HRMS(m/z): found 609.1816, calcd 609.1833 [as C₂₉H₂₈N₄O₁₁] IR (KBr,cm.sup.−1): 3415, 3353, 1749, 1652, 1575, 1540, 1375, 1197, 609. ¹H-NMR(300 MHz, DMSO-d₆, δ ppm): 11.20(1H, s), 9.78(1H, s), 9.75(1H, s),8.87(1H, d, J=8.6 Hz), 8.79(1H, d, J=8.6 Hz), 7.18(1H, d, J=2.0 Hz),6.98(1H, d, J=2.0 Hz), 6.82(1H, dd, J=2.0, 8.6 Hz), 6.80(1H, dd, J=2.0,8.6 Hz), 5.97(1H, J=8.3 Hz), 5.86(1H, d, J=3.8 Hz), 5.55(1H, d, J=2.6Hz), 5.32(1H, d, J=4.6 Hz), 5.11(1H, d, J=5.3 Hz), 4.91(1H, d, J=5.1Hz), 4.53(2H, t, J=5.4 Hz), 4.02(1H, m), 3.85-3.95(2H, m), 3.78(1H, m),3.40-3.60(6H, m), 3.20-3.30(1H, m).

What is claimed is:
 1. A process for the preparation of a compound ofFormula I,

wherein Q is O, N—R, S, or CH₂; X¹ and X² are independently selectedfrom: 1) H, 2) halogen, 3) OH, 4) CN, 5) NC, 6) CF₃, 7) (C═O)NO₂, 8)(C═O)C₁-C₆ alkyl, 9) (C═O)OC₁-C₆ alkyl, 10) OCH₂OCH₂CH₂Si(CH₃)₃, 11)NO₂, 12) 9-fluorenylmethylcarbonyl, 13) NR₅R₆, 14) OC₁-C₆ alkyl, 15)C₁-C₆ alkyl, 16) C₁-C₆ alkylenearyl, and 17) OC₁-C₆ alkylenearyl; R andR¹ are independently: 1) H, 2) (C═O)C₁-C₆ alkyl, 3) (C═O)CF₃, 4)(C═O)OC₁-C₆ alkyl, 5) 9-fluorenylmethylcarbonyl, 6) a furanose group, or7) a pyranose group,  so long as one of R and R¹ is a furanose group ora pyranose group; R² and R³ are independently OH or H, or R² and R³ aretaken together to form an oxo group; R⁴ is: 1) H, 2) C₁-C₁₀ alkyl, 3)CHO, 4) (C═O)C₁-C₁₀ alkyl, 5) (C═O)OC₁-C₁₀ alkyl, 6) C₀-C₁₀alkylenearyl, or 7) C₀-C₁₀ alkylene-NR⁵R⁶; R⁵ and R⁶ areindependently: 1) H, 2) (C₁-C₈ alkyl)-(R⁷)₂, 3) (C═O)O(C₁-C₈ alkyl), 4)9-fluorenylmethylcarbonyl, 5) OCH₂OCH₂CH₂Si(CH₃)₃, 6) (C═O)(C₁-C₈alkyl), 7) (C═O)CF₃, or 8) (C₂-C₈ alkenyl)-(R⁷)₂, or R⁵ and R⁶ are takentogether with the nitrogen to which they are attached to formN-phthalimido; R⁷ is: 1) H, 2) OH, 3) OC₁-C₆ alkyl, or 4) aryl, saidaryl optionally substituted with up to two groups selected from OH,O(C₁-C₆ alkyl), and (C₁-C₃ alkylene)-OH; which comprises the steps of:(a) reacting a furanose or a pyranose with an activating reagent toproduce an activated sugar; and (b) coupling the activated sugar with acompound of Formula IV

wherein R^(1a) is H if Q is O, S, CH₂, or N—R and R is not H, otherwiseR^(1a) is selected from R¹; in the presence of an aqueous solution ofalkali hydroxide and a phase transfer catalyst in a biphasic system toproduce the compound of Formula I.
 2. The process of claim 1, wherein Rand R¹ are independently selected from a furanose group of Formula IIAor a pyranose group of Formula IIB, when R or R¹ is defined as afuranose group or a pyranose group, respectively;

R⁸ is independently selected from: 1) hydrogen, 2) C₁-C₆ alkyl, 3) OH,4) halogen, 5) O(C₁-C₆ alkyl), 6) O(C₁-C₆ alkylene)-aryl, 7) OSO₂(C₁-C₆alkyl), 8) OSO₂aryl, 9) OCH₂OCH₂CH₂Si(CH₃)₃, 10) O(C═O)(C₁-C₆ alkyl),11) O(C═O)CF₃, 12) azido, or 13) NR⁵R⁶, or two R⁸'s on the same carbonare taken together to be oxo, ═N—R⁵, or ═N—R⁷; and the furanose orpyranose in Step (a) is a furanose of Formula IIIA or a pyranose ofFormula IIIB, respectively;


3. The process according to claim 2 wherein the activating reagent inStep (a) is selected from an acid halide and the biphasic system in Step(b) is comprised of an organic solvent selected from a hydrocarbon, anitrile, an ether, a halogenated hydrocarbon, a ketone, or an apolaraprotic solvent.
 4. The process according to claim 3 wherein theactivating reagent is selected from SOCl₂ or oxalyl chloride.
 5. Theprocess according to claim 3 wherein the biphasic system is comprised ofmethyl-t-butyl ether, dichloromethane, or trifluorotoluene.
 6. Theprocess according to claim 3 wherein the phase transfer catalyst in Step(b) is (R^(a))₄M⁺A⁻; R^(a) is independently H or C₁-C18 aliphatichydrocarbon; M is Nor P; and A is OH, F, Br, Cl, I, HSO₄, CN, MeSO₃, orPhCH₂CO₂.
 7. The process according to claim 6, wherein the phasetransfer catalyst is tricaprylmethyl ammonium chloride.
 8. The processaccording to claim 3, wherein the aqueous solution of alkali hydroxidein Step (b) has a concentration of about 5% to about 95% w/w and thealkali hydroxide is selected from lithium hydroxide, sodium hydroxide,potassium hydroxide, and cesium hydroxide.
 9. The process of claim 8wherein the aqueous solution of alkali hydroxide has a concentration ofabout 45% to about 50% w/v and the alkali hydroxide is potassiumhydroxide or sodium hydroxide.
 10. A process for the preparation of acompound of Formula V,

wherein R⁴ is: 1) H, 2) C₁-C₁₀ alkyl, 3) CHO 4) (C═O)C₁-C₁₀ alkyl, 5)(C═O)OC₁-C₁₀ alkyl, 6) C₀-C₁₀ alkylenearyl, or 7) C₀-C₁₀ alkylene-NR⁵R⁶;R⁵ and R⁶ are independently: 1) H, 2) (C₁-C₈ alkyl)-(R⁷)₂, 3)(C═O)O(C₁-C₈ alkyl), 4) 9-fluorenylmethylcarbonyl, 5)OCH₂OCH₂CH₂Si(CH₃)₃, 6) (C═O)(C₁-C₈ alkyl), 7) (C═O)CF₃, or 8) (C₂-C₈alkenyl)-(R⁷)₂, or R⁵ and R⁶ are taken together with the nitrogen towhich they are attached to form N-phthalimido; R⁷ is: 1) H, 2) OH, 3)OC₁-C₆ alkyl, or 4) aryl, said aryl optionally substituted with up totwo groups selected from OH, O(C₁-C₆ alkyl), and (C₁-C₃ alkylene)-OH; R⁹is: 1) H, 2) C₁-C₆ alkyl, 3) (C₁-C₆ alkylene)-aryl, 4) SO₂(C₁-C₆ alkyl),5) SO₂aryl, 6) CH₂OCH₂CH₂Si(CH₃)₃, 7) (C═O)(C₁-C₆ alkyl), or 8)(C═O)CF₃; which comprises the steps of: (a) reacting a sugar derivativeof Formula VI with an acid chloride to produce the activated sugar; and

(b) coupling the activated sugar with a compound of Formula VII

 in the presence of an aqueous solution of an alkali hydroxide andtricaprylmethyl ammonium chloride in t-butyl methyl ether to produce thecompound of Formula V.
 11. A process for the preparation of a compoundof Formula VIII,

which comprises the steps of: (a) reacting a sugar derivative of FormulaIX with thionyl chloride to produce the activated sugar;

(b) coupling the activated sugar with a compound of Formula X

 in the presence of an aqueous solution of potassium hydroxide or sodiumhydroxide and tricaprylmethyl ammonium chloride in t-butyl methyl etherto form the glycosidated compound XI;

(c) deprotecting the glycosidated product XI by reacting it withcatalytic palladium in the presence of hydrogen gas to form thedeprotected glycosidated product XII;

(d) reacting the deprotected glycosidated product XII with an aqueoussolution of alkali hydroxide to form anhydride XIII; and

(e) reacting anhydride XIII with 2-hydrazino-1,3-propanediol to producethe compound of Formula VIII.
 12. The process of claim 10 wherein Step(A) is conducted in t-butyl methyl ether or tetrahydrofuran at atemperature of about −10° C. to about 30° C. and Step (B) is conductedat a temperature of about 0° C. to about 40° C.
 13. The process of claim12, wherein the potassium hydroxide or sodium hydroxide in step (b) isadded before the tricaprylmethyl ammonium chloride.